Compositions for the treatment of autodigestion

ABSTRACT

Compositions for the treatment of shock, autodigestion, multi-organ failure, intestinal ischemia, or intestinal hypoperfusion are provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/069,860 filed Mar. 14, 2016, allowed, which is a continuation of U.S.application Ser. No. 14/666,926, filed Mar. 24, 2015, issued as U.S.Pat. No. 9,314,442, which claims priority to U.S. Application No.61/970,247, filed Mar. 25, 2014, and U.S. Application No. 62/019,007,filed Jun. 30, 2014, each of which is incorporated herein by referencein its entirety.

BACKGROUND OF THE INVENTION

Shock is a life-threatening condition that can result from trauma,severe blood loss, heart attacks, cardiovascular dysfunction, ischemia,sepsis, and burns. Major classes of shock include but are not limited tocardiogenic shock, hypovolemic shock, hemorrhagic shock, anaphylacticshock, neurogenic shock, and septic (or endotoxic) shock. Shock can leadto multi-organ failure (also known as multi-organ dysfunction syndrome)if immediate medical treatment is not received. Under the conditions ofshock, the intestinal barrier and walls become compromised and thedigestive enzymes that are normally contained within the intestinepermeate through the intestinal walls and enter the bloodstream, leadingto a condition known as autodigestion, in which the body's digestiveenzymes begin to digest its own tissues. Autodigestion is hypothesizedto be a mechanism for inflammation and multi-organ failure resultingfrom shock.

SUMMARY OF THE INVENTION

Despite the severity of shock, autodigestion, multi-organ failure,ischemia, and hypoperfusion, few therapies are available. Most effortshave focused on the modulation of individual inflammatory mediators ofshock, e.g., cytokines, nitric oxide, and endotoxin, to mitigate theeffects of shock. However, therapies that target particular inflammatorymediators have proven largely ineffective due to the multifaceted natureof the mediators. Thus, a need exists for therapeutics to treat shock,autodigestion, multi-organ failure, ischemia, and hypoperfusion,particularly therapeutics that preserve or help reestablish theintegrity of the intestinal wall.

Disclosed herein are compositions for the treatment of shock,autodigestion, multi-organ failure, intestinal ischemia, and/orhypoperfusion. In some embodiments, compositions disclosed hereincomprise tranexamic acid, PEG, glucose, and one or more electrolytes. Insome embodiments, the PEG is PEG 3350. In certain embodiments,compositions disclosed herein comprise a non-colonic cleansing amount ofPEG 3350. In some embodiments, compositions disclosed herein compriseabout 7.8 g of tranexamic acid, about 50.3 g of PEG 3350, about 40 g ofglucose, about 5.7 g of sodium sulfate, about 1.7 g of sodiumbicarbonate, about 1.5 g of sodium chloride, and about 0.7 g ofpotassium chloride. In some embodiments, compositions disclosed hereincomprise about 7.8 g of tranexamic acid and about 40 g of glucose. Insome embodiments, compositions disclosed herein are formulated asaqueous solutions. In certain specific embodiments, the volume of theaqueous solution is 1000 mL. In some embodiments, compositions disclosedherein comprise about 7.5 g of tranexamic acid, about 32.5 g of PEG3350, about 28 g of glucose, about 4.0 g of sodium sulfate, about 1.2 gof sodium bicarbonate, about 1.0 g of sodium chloride, and about 0.5 gof potassium chloride. In some embodiments, compositions disclosedherein comprise about 7.5 g of tranexamic acid and about 28 g ofglucose. In some embodiments, compositions disclosed herein areformulated as aqueous solutions. In certain specific embodiments, thevolume of the aqueous solution is 700 mL.

In some embodiments, compositions disclosed herein are administered forthe treatment of shock, autodigestion, multi-organ failure, intestinalischemia, or hypoperfusion. In certain specific embodiments,compositions disclosed herein are administered for the treatment ofcardiogenic shock, hemorrhagic shock, or septic shock. In someembodiments, compositions disclosed herein are administered for thetreatment of septic shock associated with or caused by sepsis. In someembodiments, compositions disclosed herein are administered for thetreatment of cardiogenic shock associated with or caused bycardiovascular surgery, myocardial infarction, arrhythmia, or mechanicalcomplications. In some embodiments, compositions disclosed herein areadministered for the treatment of hemorrhagic shock associated with orcaused by trauma. In some embodiments, compositions disclosed herein areadministered for the treatment of shock associated with or caused by ahemorrhagic virus. In some embodiments, the hemorrhagic virus is anEbola virus. In some embodiments, compositions disclosed herein areadministered orally, or via a nasogastric, orogastric, nasojejunal,orojejunal, nasoduodenal, or percutaneous endoscopic gastrostomy tube orcatheter.

In some embodiments, disclosed herein is a kit comprising: thecomponents tranexamic acid, PEG, glucose, and one or more electrolytes,wherein at least one of the components tranexamic acid, PEG, glucose,and one or more electrolytes is in a separate container from at leastone of the other components tranexamic acid, PEG, glucose, and one ormore electrolytes; and instructions to combine the components tranexamicacid, PEG, glucose, and one or more electrolytes in a singlecomposition. In some embodiments, a kit comprises tranexamic acid, PEG,and one or more electrolytes are in a first container, and glucose in asecond container. In some embodiments, a kit comprises instructions toreconstitute the components with water to provide an aqueousformulation. In some embodiments, a kit comprises a first containercomprising about 7.8 g of tranexamic acid, about 50.3 g of PEG 3350,about 5.7 g of sodium sulfate, about 1.7 g of sodium bicarbonate, about1.5 g of sodium chloride, and about 0.7 g of potassium chloride, and asecond container comprising about 40 g of glucose. In some embodiments,a kit comprises a first container comprising about 7.8 g of tranexamicacid, about 50.3 g of PEG 3350, about 5.7 g of sodium sulfate, about 1.7g of sodium bicarbonate, about 1.5 g of sodium chloride, and about 0.7 gof potassium chloride, a second container comprising about 40 g ofglucose, and instructions to reconstitute the tranexamic acid, PEG,glucose, and one or more electrolytes with water to 1000 mL. In someembodiments, a kit comprises a first container comprising about 7.5 g oftranexamic acid, about 32.5 g of PEG 3350, about 4.0 g of sodiumsulfate, about 1.2 g of sodium bicarbonate, about 1.0 g of sodiumchloride, and about 0.5 g of potassium chloride, and a second containercomprising about 28 g of glucose. In some embodiments, a kit comprises afirst container comprising about 7.5 g of tranexamic acid, about 32.5 gof PEG 3350, about 4.0 g of sodium sulfate, about 1.2 g of sodiumbicarbonate, about 1.0 g of sodium chloride, and about 0.5 g ofpotassium chloride, a second container comprising about 28 g of glucose,and instructions to reconstitute the tranexamic acid, PEG, glucose, andone or more electrolytes with water to 700 mL. In some embodiments, akit comprises instructions to administer the combined components orallyor via a nasogastric, orogastric, nasojejunal, orojejunal, nasoduodenal,or percutaneous endoscopic gastrostomy tube or catheter.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 shows a representative cross section of the small intestine froma rat treated with an enteral formulation and superior mesentery arteryocclusion (SMAO). Healthy villi are marked with n and damaged villi aremarked with d.

FIGS. 2A and 2B show the cross sections of the small intestines of ratsfollowing treatment with Representative Formulation 1 and ComparativeFormulation 1, respectively. FIG. 2A shows that rat intestinal villiappear healthy and structurally intact and that the entire length of thevilli is visible and completely covered in goblet cells, followingadministration of Representative Formulation 1 and shock inductionaccording to Example 2. FIG. 2B shows that rat intestinal villi arestructurally damaged, with missing villi tips and atypical goblet cellstaining, following administration of Comparative Formulation 1 andshock induction according to Example 2.

FIG. 3 illustrates the percentage of villi that were structurally intactwith intact epithelial lining in all rats treated in Example 2.Representative Formulation 1 preserved on average 92.6% of villi, whileComparative Formulation 1 preserved on average 52.8% of the villi. Dataare averages±SEM; n=4 rats in each group; *=p<0.01 compared torespective treated group, ANOVA.

FIGS. 4A and 4B show the cross section of the small intestine from a rattreated with Representative Formulation 2 and Comparative Formulation 2,respectively. FIG. 4A shows that villi appear healthy and structurallyintact and that the entire length of the villi is visible and completelycovered in goblet cells, following administration of RepresentativeFormulation 2 and shock induction according to Example 3. FIG. 4B showsthat rat villi are structurally damaged, with missing villi tips andatypical goblet cell staining, following administration of ComparativeFormulation 2 and shock induction according to Example 3.

FIG. 5 illustrates the percentage of villi that were structurally intactwith intact epithelial lining in all rats treated in Example 3.Representative Formulation 2 preserved on average 83.4% of villi, whileComparative Formulation 2 preserved on average 51.3% of the villi. Dataare averages±SEM; n=4 rats in each group; *=p<0.01 compared torespective treated group, ANOVA.

FIGS. 6A and 6B show the cross section of the small intestine from a rattreated with Representative Formulation 3 and Comparative Formulation 3,respectively. FIG. 6A shows that villi appear healthy and structurallyintact and that the entire length of the villi is visible and completelycovered in goblet cells, following administration of RepresentativeFormulation 3 and hemorrhagic shock induction according to Example 4.FIG. 6B shows that rat villi are structurally damaged followingadministration of Comparative Formulation 3 and hemorrhagic shockinduction according to Example 4.

FIG. 7 illustrates the percentage of villi that were structurally intactwith intact epithelial lining in all rats treated in Example 4.Representative Formulation 3 preserved on average 88.8% of villi, whileComparative Formulation 3 preserved on average 64.1% of the villi. Dataare averages±SEM; n=4 rats in each group; *=p<0.01 compared torespective treated group, ANOVA.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of skill in the artto which the inventions described herein belong. All publications,patents, and patent applications mentioned in this specification arehereby incorporated by reference to the same extent as if eachindividual publication, patent, or patent application was specificallyand individually indicated to be incorporated by reference.

Definition of Terms

When the term “about” is present before a numerical value herein, itmeans ±10% of the numerical value. For example, as used herein, the term“about 10 g” means an amount from 9 g to 11 g.

As used herein, the terms “comprising,” “including,” “such as,” and “forexample” (or “e.g.”) are used in their open, non-limiting sense.

The term “treat” and its grammatical variants (e.g., “to treat,”“treating,” and “treatment”) refer to administration of an activepharmaceutical ingredient to a patient with the purpose of amelioratingor reducing the incidence of one or more symptoms of a condition ordisease state in the patient. In some embodiments, such symptoms arechronic or acute, and such amelioration are partial or complete for someinstances. In the present context, treatment entails administering apharmaceutical composition described herein to a patient via a route ofadministration disclosed herein.

As used herein, “PEG” refers to a polyethylene glycol polymer. When“PEG” is used in combination with a numerical value, the numerical valuedefines the average molecular weight of the polyethylene glycol polymer.For an example PEG 3350 refers to a polyethylene glycol polymer that hasan average molecular weight of 3,350 Da.

As used herein, the term “non-colonic cleansing amount” refers to anamount of a substance that does not cause significant or substantiallyall removal of feces and toxins from the colon and intestinal tract whenadministered to the gastrointestinal tract.

As used herein, the terms “electrolyte” and “electrolytes” are used todescribe any substances that ionize when dissolved in an ionizingsolvent, such as water. Electrolytes include, but are not limited to,soluble salts, acids, or bases.

As used herein, the term “wt %” refers to the weight percent of a givencomponent in a composition. For example, as used herein, an aqueoussolution comprising 4 wt % glucose refers to an aqueous solution thatcomprises 4 grams of glucose per 100 grams of the solution.

Compositions

Disclosed herein are compositions for the treatment of shock,autodigestion, multi-organ failure, intestinal ischemia, orhypoperfusion. In some embodiments, compositions disclosed hereincomprise tranexamic acid. In some embodiments, the compositions compriseabout 7.0 g, about 7.1 g, about 7.2 g, about 7.3 g, about 7.4 g, about7.5 g, about 7.6 g, about 7.7 g, about 7.8 g, about 7.9 g, about 8.0 g,about 8.1 g, about 8.2 g, about 8.3 g, about 8.4 g, about 8.5 g, orabout 8.6 g of tranexamic acid. In a specific embodiment, compositionsdisclosed herein comprise about 7.8 g of tranexamic acid. In someembodiments, compositions disclosed herein comprise about 7.0 g to about8.6 g of tranexamic acid.

In some embodiments, the compositions disclosed herein comprise about6.8 g, about 6.9 g, about 7.0 g, about 7.1 g, about 7.2 g, about 7.3 g,about 7.4 g, about 7.5 g, about 7.6 g, about 7.7 g, about 7.8 g, about7.9 g, about 8.0 g, about 8.1 g, about 8.2 or about 8.3 g of tranexamicacid. In a specific embodiment, compositions disclosed herein compriseabout 7.5 g of tranexamic acid. In some embodiments, compositionsdisclosed herein comprise about 6.8 g to about 8.3 g of tranexamic acid.

In some embodiments, compositions disclosed herein comprise anon-colonic cleansing amount of PEG. In certain specific embodiments,compositions disclosed herein comprise a non-colonic cleansing amount ofPEG 2000, PEG 3000, PEG 3350, or PEG 4000. In a specific embodiment,compositions disclosed herein comprise a non-colonic cleansing amount ofPEG 3350. In some embodiments, a non-colonic cleansing amount of PEG,e.g., PEG 3350, is about 33.9 g, about 34.0 g, about 34.1 g, about 34.2g, about 34.3 g, about 34.4 g, about 34.5 g, about 34.6 g, about 34.7 g,about 34.8 g, about 34.9 g, about 35.0 g, about 35.1 g, about 35.2 g,about 35.3 g, about 35.4 g, about 35.5 g, about 35.6 g, about 35.7 g,about 35.8 g, about 35.9 g, about 36.0 g, about 36.1 g, about 36.2 g,about 36.3 g, about 36.4 g, about 36.5 g, about 36.6 g, about 36.7 g,about 36.8 g, about 36.9 g, about 37.0 g, about 37.1 g, about 37.2 g,about 37.3 g, about 37.4 g, about 37.5 g, about 37.6 g, about 37.7 g,about 37.8 g, about 37.9 g, about 38.0 g, about 38.1 g, about 38.2 g,about 38.3 g, about 38.4 g, about 38.5 g, about 38.6 g, about 38.7 g,about 38.8 g, about 38.9 g, about 39.0 g, about 39.1 g, about 39.2 g,about 39.3 g, about 39.4 g, about 39.5 g, about 39.6 g, about 39.7 g,about 39.8 g, about 39.9 g, about 40.0 g, about 40.1 g, about 40.2 g,about 40.3 g, about 40.4 g, about 40.5 g, about 40.6 g, about 40.7 g,about 40.8 g, about 40.9 g, about 41.0 g, about 41.1 g, about 41.2,about 41.3 g, about 41.4 g, about 41.5 g, about 41.6 g, about 41.7 g,about 41.8 g, about 41.9 g, about 42.0 g, about 42.1 g, about 42.2 g,about 42.3 g, about 42.4 g, about 42.5 g, about 42.6 g, about 42.7 g,about 42.8 g, about 42.9 g, about 43.0 g, about 43.1 g, about 43.2 g,about 43.3 g, about 43.4 g, about 43.5 g, about 43.6 g, about 43.7 g,about 43.8 g, about 43.9 g, about 44.0 g, about 44.1 g, about 44.2 g,about 44.3 g, about 44.4 g, about 44.5 g, about 44.6 g, about 44.7 g,about 44.8 g, about 44.9 g, about 45.0 g, about 45.1 g, about 45.2 g,about 45.3 g, about 45.4 g, about 45.5 g, about 45.6 g, about 45.7 g,about 45.8 g, about 45.9 g, about 46.0 g, about 46.1 g, about 46.2 g,about 46.3 g, about 46.4 g, about 46.5 g, about 46.6 g, about 46.7 g,about 46.8 g, about 46.9 g, about 47.0 g, about 47.1 g, about 47.2 g,about 47.3 g, about 47.4 g, about 47.5 g, about 47.6 g, about 47.7 g,about 47.8 g, about 47.9 g, about 48.0 g, about 48.1 g, about 48.2 g,about 48.3 g, about 48.4 g, about 48.5 g, about 48.6 g, about 48.7 g,about 48.8 g, about 48.9 g, about 49.0 g, about 49.1 g, about 49.2 g,about 49.3 g, about 49.4 g, about 49.5 g, about 49.6 g, about 49.7 g,about 49.8 g, about 49.9 g, about 50.0 g, about 50.1 g, about 50.2 g,about 50.3 g, about 50.4 g, about 50.5 g, about 50.6 g, about 50.7 g,about 50.8 g, about 50.9 g, about 51.0 g, about 51.1 g, about 51.2 g,about 51.3 g, about 51.4 g, about 51.5 g, about 51.6 g, about 51.7 g,about 51.8 g, about 51.9 g, about 52.0 g, about 52.1 g, about 52.2 g,about 52.3 g, about 52.4 g, about 52.5 g, about 52.6 g, about 52.7 g,about 52.8 g, about 52.9 g, about 53.0 g, about 53.1 g, about 53.2 g,about 53.3 g, about 53.4 g, about 53.5 g, about 53.6 g, about 53.7 g,about 53.8 g, about 53.9 g, about 54.0 g, about 54.1 g, about 54.2 g,about 54.3 g, about 54.4 g, about 54.5 g, about 54.6 g, about 54.7 g,about 54.8 g, about 54.9 g, about 55.0 g, about 55.1 g, about 55.2 g, orabout 55.3 g. In a specific embodiment, a non-colonic cleansing amountof PEG, e.g., PEG 3350 is about 50.3 g. In some embodiments, anon-colonic cleansing amount of PEG, e.g., PEG 3350, is about 45.2 g toabout 55.3 g. In a specific embodiment, a non-colonic cleansing amountof PEG, e.g., PEG 3350 is about 37.7 g. In some embodiments, anon-colonic cleansing amount of PEG, e.g., PEG 3350, is about 33.9 g toabout 41.5 g. In a specific embodiment, a non-colonic cleansing amountof PEG, e.g., PEG 3350 is about 40.2 g. In some embodiments, anon-colonic cleansing amount of PEG, e.g., PEG 3350, is about 36.2 g toabout 44.2 g.

In some embodiments, a non-colonic cleansing amount of PEG, e.g., PEG3350, is about 29.3 g, about 29.4 g, about 29.5 g, about 29.6 g, about29.7 g, about 29.8 g, about 29.9 g, about 30.0 g, about 30.1 g, about30.2 g, about 30.3 g, about 30.4 g, about 30.5 g, about 30.6 g, about30.7 g, about 30.8 g, about 30.9 g, about 31.0 g, about 31.1 g, about31.2 g, about 31.3 g, about 31.4 g, about 31.5 g, about 31.6 g, about31.7 g, about 31.8 g, about 31.9 g, about 32.0 g, about 32.1 g, about32.2 g, about 32.3 g, about 32.4 g, about 32.5 g, about 32.6 g, about32.7 g, about 32.8 g, about 32.9 g, about 33.0 g, about 33.1 g, about33.2 g, about 33.3 g, about 33.4 g, about 33.5 g, about 33.6 g, about33.7 g, about 33.8 g, about 33.9 g, about 34.0 g, about 34.1 g, about34.2 g, about 34.3 g, about 34.4 g, about 34.5 g, about 34.6 g, about34.7 g, about 34.8 g, about 34.9 g, about 35.0 g, about 35.1 g, about35.2 g, about 35.3 g, about 35.4 g, about 35.5 g, about 35.6 g, about35.7 g, or about 35.8 g. In a specific embodiment, a non-coloniccleansing amount of PEG, e.g., PEG 3350 is about 32.5 g. In someembodiments, a non-colonic cleansing amount of PEG, e.g., PEG 3350, isabout 29.3 g to about 35.8 g.

In some embodiments, compositions disclosed herein are formulated asaqueous solutions comprising about 4.5 wt %, about 4.6 wt %, about 4.7wt %, about 4.8 wt %, about 4.9 wt %, about 5.0 wt %, about 5.1 wt %,about 5.2 wt %, about 5.3 wt %, about 5.4 wt %, or about 5.5 wt % ofPEG. In certain embodiments, compositions disclosed herein areformulated as aqueous solutions comprising about 4.5 wt %, about 4.6 wt%, about 4.7 wt %, about 4.8 wt %, about 4.9 wt %, about 5.0 wt %, about5.1 wt %, about 5.2 wt %, about 5.3 wt %, about 5.4 wt %, or about 5.5wt % of PEG 3350. In a specific embodiment, compositions disclosedherein are formulated as aqueous solutions comprising about 5.0 wt % ofPEG. In certain embodiments, compositions disclosed herein areformulated as aqueous solutions comprising about 4.5 wt % to about 5.5wt % of PEG. In a specific embodiment, compositions disclosed herein areformulated as aqueous solutions comprising about 5.0 wt % of PEG 3350.In certain embodiments, compositions disclosed herein are formulated asaqueous solutions comprising about 4.5 wt % to about 5.5 wt % of PEG3350.

In some embodiments, compositions disclosed herein are formulated asaqueous solutions comprising about 4.2 wt %, about 4.3 wt %, about 4.4wt %, about 4.5 wt %, about 4.6 wt %, about 4.7 wt %, about 4.8 wt %,about 4.9 wt %, about 5.0 wt %, or about 5.1 wt % of PEG. In someembodiments, compositions disclosed herein are formulated as aqueoussolutions comprising about 4.2 wt %, about 4.3 wt %, about 4.4 wt %,about 4.5 wt %, about 4.6 wt %, about 4.7 wt %, about 4.8 wt %, about4.9 wt %, about 5.0 wt %, or about 5.1 wt % of PEG 3350. In a specificembodiment, compositions disclosed herein are formulated as aqueoussolutions comprising about 4.6 wt % of PEG. In certain embodiments,compositions disclosed herein are formulated as aqueous solutionscomprising about 4.2 wt % to about 5.1 wt % of PEG. In a specificembodiment, compositions disclosed herein are formulated as aqueoussolutions comprising about 4.6 wt % of PEG 3350. In certain embodiments,compositions disclosed herein are formulated as aqueous solutionscomprising about 4.2 wt % to about 5.1 wt % of PEG 3350.

In some embodiments, compositions disclosed herein comprise glucose. Insome embodiments, compositions disclosed herein comprise about 19 g,about 20 g, about 21 g, about 22 g, about 23 g, about 24 g, about 25 g,about 26 g, about 27 g, about 28 g, about 29 g, about 30 g, about 31 g,about 32 g, about 33 g, about 34 g, about 35 g, about 36 g, about 37 g,about 38 g, about 39 g, about 40 g, about 41 g, about 42 g, about 43 g,about 44 g, about 45 g, about 46 g, about 47 g, about 48 g, about 49 g,about 50 g, about 51 g, about 52 g, about 53 g, about 54 g, about 55 g,about 56 g, about 57 g, about 58 g, about 59 g, or about 60 g ofglucose. In a specific embodiment, compositions disclosed hereincomprise about 40 g of glucose. In certain embodiments, compositionsdisclosed herein comprise about 25 g to about 60 g of glucose, or about25 g to about 50 g of glucose. In a specific embodiment, compositionsdisclosed herein comprise about 30 g of glucose. In certain embodiments,compositions disclosed herein comprise about 19 g to about 45 g ofglucose, or about 19 g to about 38 g of glucose. In a specificembodiment, compositions disclosed herein comprise about 32 g ofglucose. In certain embodiments, compositions disclosed herein compriseabout 20 g to about 48 g of glucose, or about 20 g to about 40 g ofglucose.

In some embodiments, compositions disclosed herein comprise about 25 g,about 26 g, about 27 g, about 28 g, about 29 g, about 30 g, or about 31g of glucose. In a specific embodiment, compositions disclosed hereincomprise about 28 g of glucose. In certain embodiments, compositionsdisclosed herein comprise about 25 g to about 31 g of glucose

In some embodiments, compositions disclosed herein are formulated asaqueous solutions comprising about 2.5 wt %, about 2.6 wt %, about 2.7wt %, about 2.8 wt %, about 2.9 wt %, about 3.0 wt %, about 3.1 wt %,about 3.2 wt %, about 3.3 wt %, about 3.4 wt %, about 3.5 wt %, about3.6 wt %, about 3.7 wt %, about 3.8 wt %, about 3.9 wt %, about 4.0 wt%, about 4.1 wt %, about 4.2 wt %, about 4.3 wt %, about 4.4 wt %, about4.5 wt %, about 4.6 wt %, about 4.7 wt %, about 4.8 wt %, about 4.9 wt%, about 5.0 wt %, about 5.1 wt %, about 5.2 wt %, about 5.3 wt %, about5.4 wt %, about 5.5 wt %, about 5.6 wt %, about 5.7 wt %, about 5.8 wt%, about 5.9 wt % or about 6.0 wt % of glucose. In a specificembodiment, compositions disclosed herein are formulated as aqueoussolutions comprising about 4 wt % of glucose. In certain embodiments,compositions disclosed herein are formulated as aqueous solutionscomprising about 2.5 wt % to about 6.0 wt % of glucose, or about 2.5 wt% to about 5.0 wt % of glucose.

In some embodiments, compositions disclosed herein are formulated asaqueous solutions comprising about 3.6 wt %, about 3.7 wt %, about 3.8wt %, about 3.9 wt %, about 4.0 wt %, about 4.1 wt %, about 4.2 wt %,about 4.3 wt %, or about 4.4 wt % of glucose. In a specific embodiment,compositions disclosed herein are formulated as aqueous solutionscomprising about 4 wt % of glucose. In certain embodiments, compositionsdisclosed herein are formulated as aqueous solutions comprising about3.6 wt % to about 4.4 wt % of glucose.

In some embodiments, compositions disclosed herein comprise one or moreelectrolytes. In certain embodiments, the one or more electrolytescomprise sodium chloride (NaCl). In some embodiments, compositionsdisclosed herein comprise about 1.0 g, about 1.1 g, about 1.2 g, about1.3 g, about 1.4 g, about 1.5 g, about 1.6 g, or about 1.7 of sodiumchloride. In a specific embodiment, compositions disclosed hereincomprise about 1.5 g of sodium chloride. In some embodiments,compositions disclosed herein comprise about 1.3 g to about 1.7 g ofsodium chloride. In a specific embodiment, compositions disclosed hereincomprise about 1.1 g of sodium chloride. In some embodiments,compositions disclosed herein comprise about 1.0 g to about 1.2 g ofsodium chloride. In a specific embodiment, compositions disclosed hereincomprise about 1.2 g of sodium chloride. In some embodiments,compositions disclosed herein comprise about 1.1 g to about 1.3 g ofsodium chloride.

In some embodiments, compositions disclosed herein comprise about 0.9 g,about 1.0 g, or about 1.1 g of sodium chloride. In a specificembodiment, compositions disclosed herein comprise about 1.0 g of sodiumchloride. In some embodiments, compositions disclosed herein compriseabout 0.9 g to about 1.1 g of sodium chloride.

In some embodiments, compositions disclosed herein are formulated asaqueous solutions comprising about 0.13 wt %, about 0.14 wt %, about0.15 wt %, about 0.16 wt %, about 0.17 wt % of sodium chloride. In aspecific embodiment, compositions disclosed herein are formulated asaqueous solutions comprising about 0.15 wt % of sodium chloride. In someembodiments, compositions disclosed herein are formulated as aqueoussolutions comprising about 0.13 wt % to about 0.17 wt % of sodiumchloride.

In some embodiments, the one or more electrolytes comprise sodiumsulfate (Na₂SO₄). In some embodiments, compositions disclosed hereincomprise about 3.9 g, about 4.0 g, about 4.1 g, about 4.2 g, about 4.3g, about 4.4 g, about 4.5 g, about 4.6 g, about 4.7 g, about 4.8 g,about 4.9 g, about 5.0 g, about 5.1 g, about 5.2 g, about 5.3 g, about5.4 g, about 5.5 g, about 5.6 g, about 5.7 g, about 5.8 g, about 5.9 g,about 6.0 g, about 6.1 g, about 6.2 or about 6.3 g of sodium sulfate. Ina specific embodiment, compositions disclosed herein comprise about 5.7g of sodium sulfate. In some embodiments, compositions disclosed hereincomprise about 5.1 g to about 6.3 g of sodium sulfate. In a specificembodiment, compositions disclosed herein comprise about 4.3 g of sodiumsulfate. In some embodiments, compositions disclosed herein compriseabout 3.9 g to about 4.7 g of sodium sulfate. In a specific embodiment,compositions disclosed herein comprise about 4.6 g of sodium sulfate. Insome embodiments, compositions disclosed herein comprise about 4.1 g toabout 5.1 g of sodium sulfate.

In some embodiments, compositions disclosed herein comprise about 3.6 g,about 3.7 g, about 3.8 g, about 3.9 g, about 4.0 g, about 4.1 g, about4.2 g, about 4.3 g, or about 4.4 g of sodium sulfate. In a specificembodiment, compositions disclosed herein comprise about 4.0 g of sodiumsulfate. In some embodiments, compositions disclosed herein compriseabout 3.6 g to about 4.4 g of sodium sulfate.

In some embodiments, compositions disclosed herein are formulated asaqueous solutions comprising sodium sulfate. In some embodiments, thecompositions disclosed herein are formulated as aqueous solutionscomprising about 0.51 wt %, about 0.52 wt %, about 0.53 wt %, about 0.54wt %, about 0.55 wt %, about 0.56 wt %, about 0.57 wt %, about 0.58 wt%, about 0.59 wt %, about 0.60 wt %, about 0.61 wt %, about 0.62 wt %,or about 0.63 wt % of sodium sulfate. In a specific embodiment,compositions disclosed herein are formulated as aqueous solutionscomprising about 0.57 wt % of sodium sulfate. In some embodiments,compositions disclosed herein are formulated as aqueous solutionscomprising about 0.51 wt % to about 0.63 wt % of sodium sulfate.

In some embodiments, the one or more electrolytes comprise sodiumbicarbonate (NaHCO₃). In some embodiments, compositions disclosed hereincomprise about 1.2 g, about 1.3 g, about 1.4 g, about 1.5 g, about 1.6g, about 1.7 g, about 1.8 g, or about 1.9 g of sodium bicarbonate. In aspecific embodiment, compositions disclosed herein comprise about 1.7 gof sodium bicarbonate. In some embodiments, compositions disclosedherein comprise about 1.5 g to about 1.9 g of sodium bicarbonate. In aspecific embodiment, compositions disclosed herein comprise about 1.3 gof sodium bicarbonate. In some embodiments, compositions disclosedherein comprise about 1.2 g to about 1.4 g of sodium bicarbonate. In aspecific embodiment, compositions disclosed herein comprise about 1.4 gof sodium bicarbonate. In some embodiments, compositions disclosedherein comprise about 1.3 g to about 1.5 g of sodium bicarbonate.

In some embodiments, compositions disclosed herein comprise about 1.1 g,about 1.2 g, or about 1.3 g of sodium bicarbonate. In a specificembodiment, compositions disclosed herein comprise about 1.2 g of sodiumbicarbonate. In some embodiments, compositions disclosed herein compriseabout 1.1 g to about 1.3 g of sodium bicarbonate.

In some embodiments, compositions disclosed herein are formulated asaqueous solutions comprising about 0.15 wt %, about 0.16 wt %, about0.17 wt %, about 0.18 wt %, or about 0.19 wt % of sodium bicarbonate. Ina specific embodiment, compositions disclosed herein are formulated asaqueous solutions comprising about 0.17 wt % of sodium bicarbonate. Insome embodiments, compositions disclosed herein are formulated asaqueous solutions comprising about 0.15 wt % to about 0.19 wt % ofsodium bicarbonate.

In some embodiments, compositions disclosed herein are formulated asaqueous solutions comprising about 0.16 wt %, about 0.17 wt %, about0.18 wt %, or about 0.19 wt % of sodium bicarbonate. In a specificembodiment, compositions disclosed herein are formulated as aqueoussolutions comprising about 0.17 wt % of sodium bicarbonate. In someembodiments, compositions disclosed herein are formulated as aqueoussolutions comprising about 0.16 wt % to about 0.19 wt % of sodiumbicarbonate.

In some embodiments, the one or more electrolytes comprise potassiumchloride (KC1). In some embodiments, compositions disclosed hereincomprise about 0.4 g, about 0.5 g, about 0.6 g, about 0.7 g or about 0.8g of potassium chloride. In a specific embodiment, compositionsdisclosed herein comprise about 0.7 g of potassium chloride. In someembodiments, compositions disclosed herein comprise about 0.6 g to about0.8 g of potassium chloride. In a specific embodiment, compositionsdisclosed herein comprise about 0.5 g of potassium chloride. In someembodiments, compositions disclosed herein comprise about 0.4 g to about0.6 g of potassium chloride. In a specific embodiment, compositionsdisclosed herein comprise about 0.6 g of potassium chloride. In someembodiments, compositions disclosed herein comprise about 0.5 g to about0.7 g of potassium chloride.

In some embodiments, compositions disclosed herein comprise about 0.4 g,about 0.5 g, or about 0.6 g of potassium chloride. In a specificembodiment, compositions disclosed herein comprise about 0.5 g ofpotassium chloride. In some embodiments, compositions disclosed hereincomprise about 0.4 g to about 0.6 g of potassium chloride.

In some embodiments, compositions disclosed herein are formulated asaqueous solutions comprising about 0.06 wt %, about 0.07 wt %, or about0.08 wt % of potassium chloride. In a specific embodiment, compositionsdisclosed herein are formulated as aqueous solutions comprising about0.07 wt % of potassium chloride. In some embodiments, compositionsdisclosed herein are formulated as aqueous solutions comprising about0.06 wt % to about 0.08 wt % of potassium chloride.

In some embodiments, compositions disclosed herein are formulated asaqueous solutions comprising about 0.06 wt %, about 0.07 wt %, about0.08 wt %, or about 0.09% wt of potassium chloride. In a specificembodiment, compositions disclosed herein are formulated as aqueoussolutions comprising about 0.07 wt % of potassium chloride. In someembodiments, compositions disclosed herein are formulated as aqueoussolutions comprising about 0.06 wt % to about 0.09 wt % of potassiumchloride.

In some embodiments, the compositions disclosed herein are formulatedinto any suitable dosage form, including but not limited to solutions,dispersions, self-emulsifying dispersions, solid solutions, liposomaldispersions, liquids, gels, syrups, elixirs, lyophilized formulations,powders, or multiparticulate formulations. Such formulations areoptionally manufactured in a conventional manner, such as, by way ofexample only, conventional mixing, dissolving, emulsifying, and thelike. In some embodiments, compositions disclosed herein are formulatedas a powder for reconstitution. In some embodiments, compositionsdisclosed herein are formulated as an aqueous solution.

In certain embodiments, compositions disclosed herein are formulated asa solution, e.g., an aqueous solution. In some embodiments, compositionsdisclosed herein are formulated as a solution, e.g., an aqueoussolution, having a volume of about 500 mL, about 510 mL, about 520 mL,about 530 mL, about 540 mL, about 550 mL, about 560 mL, about 570 mL,about 580 mL, about 590 mL, about 600 mL, about 610 mL, about 620 mL,about 630 mL, about 640 mL, about 650 mL, about 660 mL, about 670 mL,about 680 mL, about 690 mL, about 700 mL, about 710 mL, about 720 mL,about 730 mL, about 740 mL, about 750 mL, about 760 mL, about 770 mL,about 780 mL, about 790 mL, about 800 mL, about 810 mL, about 820 mL,about 830 mL, about 840 mL, about 850 mL, about 860 mL, about 870 mL,about 880 mL, about 890 mL, about 900 mL, about 910 mL, about 920 mL,about 930 mL, about 940 mL, about 950 mL, about 960 mL, about 970 mL,about 980 mL, about 990 mL, or about 1000 mL. In some embodiments,compositions disclosed herein are formulated as a solution, e.g., anaqueous solution, having a volume of about 500 mL to about 1000 mL. Insome embodiments, compositions disclosed herein are formulated as asolution, e.g., an aqueous solution, having a volume of about 750 mL toabout 1000 mL.

In some embodiments, compositions disclosed herein are formulated as asolution, e.g., an aqueous solution, having a volume of about 630 mL,about 640 mL, about 650 mL, about 660 mL, about 670 mL, about 680 mL,about 690 mL, about 700 mL, about 710 mL, about 720 mL, about 730 mL,about 740 mL, about 750 mL, about 760 mL, or about 770 mL. In a specificembodiment, compositions disclosed herein are formulated as a solution,e.g., an aqueous solution, having a volume of about 700 mL. In someembodiments, compositions disclosed herein are formulated as a solution,e.g., an aqueous solution, having a volume of about 630 mL to about 770mL.

In some embodiments, compositions disclosed herein comprise about 7.0 gto about 8.6 g of tranexamic acid and about 25 g to about 60 g ofglucose. In some embodiments, compositions disclosed herein compriseabout 7.0 g to about 8.6 g of tranexamic acid and about 25 g to about 50g of glucose. In certain specific embodiments, compositions disclosedherein comprise about 7.8 g of tranexamic acid and about 19 g, about 20g, about 21 g, about 22 g, about 23 g, about 24 g, about 25 g, about 26g, about 27 g, about 28 g, about 29 g, about 30 g, about 31 g, about 32g, about 33 g, about 34 g, about 35 g, about 36 g, about 37 g, about 38g, about 39 g, about 40 g, about 41 g, about 42 g, about 43 g, about 44g, about 45 g, about 46 g, about 47 g, about 48 g, about 49 g, about 50g, about 51 g, about 52 g, about 53 g, about 54 g, about 55 g, about 56g, about 57 g, about 58 g, about 59 g, or about 60 g of glucose. In aspecific embodiment, compositions disclosed herein comprise about 7.8 gof tranexamic acid and about 40 g of glucose.

In some embodiments, compositions disclosed herein comprise about 6.8 gto about 8.3 g of tranexamic acid and about 25 g to about 31 g ofglucose. In certain specific embodiments, compositions disclosed hereincomprise about 7.5 g of tranexamic acid and about 25 g, about 26 g,about 27 g, about 28 g, about 29 g, about 30 g, or about 31 g ofglucose. In a specific embodiment, compositions disclosed hereincomprise about 7.5 g of tranexamic acid and about 28 g of glucose.

In some embodiments, compositions disclosed herein comprise about 7.0 gto about 8.6 g of tranexamic acid and about 45.2 g to about 55.3 g ofPEG 3350. In some embodiments, compositions disclosed herein compriseabout 7.0 g to about 8.6 g of tranexamic acid and about 33.9 g to about41.5 g of PEG 3350. In some embodiments, compositions disclosed hereincomprise about 7.0 g to about 8.6 g of tranexamic acid and about 36.2 gto about 44.2 g of PEG 3350. In certain specific embodiments,compositions disclosed herein comprise about 7.8 g of tranexamic acidand about 33.9 g, about 34.0 g, about 34.1 g, about 34.2 g, about 34.3g, about 34.4 g, about 34.5 g, about 34.6 g, about 34.7 g, about 34.8 g,about 34.9 g, about 35.0 g, about 35.1 g, about 35.2 g, about 35.3 g,about 35.4 g, about 35.5 g, about 35.6 g, about 35.7 g, about 35.8 g,about 35.9 g, about 36.0 g, about 36.1 g, about 36.2 g, about 36.3 g,about 36.4 g, about 36.5 g, about 36.6 g, about 36.7 g, about 36.8 g,about 36.9 g, about 37.0 g, about 37.1 g, about 37.2 g, about 37.3 g,about 37.4 g, about 37.5 g, about 37.6 g, about 37.7 g, about 37.8 g,about 37.9 g, about 38.0 g, about 38.1 g, about 38.2 g, about 38.3 g,about 38.4 g, about 38.5 g, about 38.6 g, about 38.7 g, about 38.8 g,about 38.9 g, about 39.0 g, about 39.1 g, about 39.2 g, about 39.3 g,about 39.4 g, about 39.5 g, about 39.6 g, about 39.7 g, about 39.8 g,about 39.9 g, about 40.0 g, about 40.1 g, about 40.2 g, about 40.3 g,about 40.4 g, about 40.5 g, about 40.6 g, about 40.7 g, about 40.8 g,about 40.9 g, about 41.0 g, about 41.1 g, about 41.2, about 41.3 g,about 41.4 g, about 41.5 g, about 41.6 g, about 41.7 g, about 41.8 g,about 41.9 g, about 42.0 g, about 42.1 g, about 42.2 g, about 42.3 g,about 42.4 g, about 42.5 g, about 42.6 g, about 42.7 g, about 42.8 g,about 42.9 g, about 43.0 g, about 43.1 g, about 43.2 g, about 43.3 g,about 43.4 g, about 43.5 g, about 43.6 g, about 43.7 g, about 43.8 g,about 43.9 g, about 44.0 g, about 44.1 g, about 44.2 g, about 44.3 g,about 44.4 g, about 44.5 g, about 44.6 g, about 44.7 g, about 44.8 g,about 44.9 g, about 45.0 g, about 45.1 g, about 45.2 g, about 45.3 g,about 45.4 g, about 45.5 g, about 45.6 g, about 45.7 g, about 45.8 g,about 45.9 g, about 46.0 g, about 46.1 g, about 46.2 g, about 46.3 g,about 46.4 g, about 46.5 g, about 46.6 g, about 46.7 g, about 46.8 g,about 46.9 g, about 47.0 g, about 47.1 g, about 47.2 g, about 47.3 g,about 47.4 g, about 47.5 g, about 47.6 g, about 47.7 g, about 47.8 g,about 47.9 g, about 48.0 g, about 48.1 g, about 48.2 g, about 48.3 g,about 48.4 g, about 48.5 g, about 48.6 g, about 48.7 g, about 48.8 g,about 48.9 g, about 49.0 g, about 49.1 g, about 49.2 g, about 49.3 g,about 49.4 g, about 49.5 g, about 49.6 g, about 49.7 g, about 49.8 g,about 49.9 g, about 50.0 g, about 50.1 g, about 50.2 g, about 50.3 g,about 50.4 g, about 50.5 g, about 50.6 g, about 50.7 g, about 50.8 g,about 50.9 g, about 51.0 g, about 51.1 g, about 51.2 g, about 51.3 g,about 51.4 g, about 51.5 g, about 51.6 g, about 51.7 g, about 51.8 g,about 51.9 g, about 52.0 g, about 52.1 g, about 52.2 g, about 52.3 g,about 52.4 g, about 52.5 g, about 52.6 g, about 52.7 g, about 52.8 g,about 52.9 g, about 53.0 g, about 53.1 g, about 53.2 g, about 53.3 g,about 53.4 g, about 53.5 g, about 53.6 g, about 53.7 g, about 53.8 g,about 53.9 g, about 54.0 g, about 54.1 g, about 54.2 g, about 54.3 g,about 54.4 g, about 54.5 g, about 54.6 g, about 54.7 g, about 54.8 g,about 54.9 g, about 55.0 g, about 55.1 g, about 55.2 g, or about 55.3 gof PEG 3350. In a specific embodiment, compositions disclosed hereincomprise about 7.8 g of tranexamic acid and about 59.0 g of PEG 3350. Ina specific embodiment, compositions disclosed herein comprise about 7.8g of tranexamic acid and about 40.2 g of PEG 3350. In a specificembodiment, compositions disclosed herein comprise about 7.8 g oftranexamic acid and about 37.7 g of PEG 3350.

In some embodiments, compositions disclosed herein comprise about 6.8 gto about 8.3 g of tranexamic acid and about 29.3 g to about 35.8 g ofPEG 3350. In certain specific embodiments, compositions disclosed hereincomprise about 7.5 g of tranexamic acid and about 29.3 g, about 29.4 g,about 29.5 g, about 29.6 g, about 29.7 g, about 29.8 g, about 29.9 g,about 30.0 g, about 30.1 g, about 30.2 g, about 30.3 g, about 30.4 g,about 30.5 g, about 30.6 g, about 30.7 g, about 30.8 g, about 30.9 g,about 31.0 g, about 31.1 g, about 31.2 g, about 31.3 g, about 31.4 g,about 31.5 g, about 31.6 g, about 31.7 g, about 31.8 g, about 31.9 g,about 32.0 g, about 32.1 g, about 32.2 g, about 32.3 g, about 32.4 g,about 32.5 g, about 32.6 g, about 32.7 g, about 32.8 g, about 32.9 g,about 33.0 g, about 33.1 g, about 33.2 g, about 33.3 g, about 33.4 g,about 33.5 g, about 33.6 g, about 33.7 g, about 33.8 g, about 33.9 g,about 34.0 g, about 34.1 g, about 34.2 g, about 34.3 g, about 34.4 g,about 34.5 g, about 34.6 g, about 34.7 g, about 34.8 g, about 34.9 g,about 35.0 g, about 35.1 g, about 35.2 g, about 35.3 g, about 35.4 g,about 35.5 g, about 35.6 g, about 35.7 g, or about 35.8 g of PEG 3350.In a specific embodiment, compositions disclosed herein comprise about7.5 g of tranexamic acid and about 32.5 g of PEG 3350.

In some embodiments, compositions disclosed herein are formulated asaqueous solutions comprising about 7.0 g to about 8.6 g of tranexamicacid, about 4.5 wt % to about 5.5 wt % of PEG 3350, about 2.5 wt % toabout 6 wt % of glucose, about 0.51 wt % to about 0.63 wt % of sodiumsulfate, about 0.15 wt % to about 0.19 wt % of sodium bicarbonate, about0.13 wt % to about 0.17 wt % of sodium chloride, and about 0.06 wt % toabout 0.08 wt % of potassium chloride. In some embodiments, compositionsdisclosed herein are formulated as aqueous solutions comprising about7.0 g to about 8.6 g of tranexamic acid, about 4.5 wt % to about 5.5 wt% of PEG 3350, about 2.5 wt % to about 5 wt % of glucose, about 0.51 wt% to about 0.63 wt % of sodium sulfate, about 0.15 wt % to about 0.19 wt% of sodium bicarbonate, about 0.13 wt % to about 0.17 wt % of sodiumchloride, and about 0.06 wt % to about 0.08 wt % of potassium chloride.In a specific embodiment, compositions disclosed herein are formulatedas aqueous solutions comprising about 7.8 g of tranexamic acid, about5.0 wt % of PEG 3350, about 4 wt % of glucose, about 0.57 wt % of sodiumsulfate, about 0.17 wt % of sodium bicarbonate, about 0.15 wt % ofsodium chloride, and about 0.07 wt % of potassium chloride.

In some embodiments, compositions disclosed herein are formulated asaqueous solutions comprising about 6.8 g to about 8.3 g of tranexamicacid, about 4.2 wt % to about 5.1 wt % of PEG 3350, about 3.6 wt % toabout 4.4 wt % of glucose, about 0.51 wt % to about 0.63 wt % of sodiumsulfate, about 0.16 wt % to about 0.19 wt % of sodium bicarbonate, about0.13 wt % to about 0.17 wt % of sodium chloride, and about 0.06 wt % toabout 0.09 wt % of potassium chloride. In a specific embodiment,compositions disclosed herein are formulated as aqueous solutionscomprising about 7.5 g of tranexamic acid, about 4.6 wt % of PEG 3350,about 4 wt % of glucose, about 0.57 wt % of sodium sulfate, about 0.17wt % of sodium bicarbonate, about 0.15 wt % of sodium chloride, andabout 0.07 wt % of potassium chloride.

In some embodiments, the compositions disclosed herein are formulatedwith one or more inactive ingredients or pharmaceutical excipients thatprovide suitable properties of the formulation. Such inactiveingredients include but are not limited to antioxidants, carriers,viscosity modulating agents, diluents, flavoring agents, preservatives,solubilizers, stabilizers, suspending agents, and surfactants. Anysuitable amounts of such inactive ingredients are determined accordingto the particular properties desired.

Methods of Treatment

In some embodiments, the compositions disclosed herein are administeredfor the treatment of shock, autodigestion, multi-organ failure,ischemia, or hypoperfusion. In certain specific embodiments,compositions disclosed herein are administered for the treatment ofcardiogenic shock, hemorrhagic shock, or septic shock. In someembodiments, ischemia is intestinal ischemia. In some embodiments,compositions disclosed herein are administered for the treatment ofseptic shock associated with or caused by sepsis. In some embodiments,compositions disclosed herein are administered for the treatment ofcardiovascular shock associated with or caused by cardiovascularsurgery, myocardial infarction, arrhythmia, or mechanical complications.In some embodiments, a mechanical complication is a cardiovascularmechanical complication. In some embodiments, compositions disclosedherein are administered for the treatment of cardiovascular shockassociated with or caused by myocardial infarction or mechanicalcomplications. In some embodiments, compositions disclosed herein areadministered for the treatment of hemorrhagic or hypovolemic shockassociated with or caused by trauma. In some embodiments, compositionsdisclosed herein may be administered for the treatment of hemorrhagic orhypovolemic shock associated with or caused by Ebola Virus Disease orother hemorrhagic virus. In some embodiments, compositions disclosedherein are administered for the treatment of intestinal ischemia orhypoperfusion that result in shock. In some embodiments, compositionsdisclosed herein may be administered for the treatment of InflammatoryBowel Disease or Crohn's Disease, or complications arising fromInflammatory Bowel Disease or Crohn's Disease. In some embodiments,compositions disclosed herein may be administered for the treatment ofClostridium difficile colitis, or complications that arise fromClostridium difficile colitis.

In some embodiments, the compositions disclosed herein are administeredto a subject, e.g., a human, by multiple administration routes, eitheralone or concurrently, including but not limited to oral, nasogastric,orogastric, nasojejunal, orojejunal, nasoduodenal, or percutaneousendoscopic gastrostomy administration or other enteral routes. In someembodiments, compositions disclosed herein are administered directly tothe gastrointestinal tract. In some embodiments, compositions disclosedherein are administered to the stomach. In some embodiments,compositions disclosed herein are administered to the small intestine.In certain embodiments, compositions disclosed herein are administeredvia a nasogastic, orogastic, nasojejunal, orojejunal, nasoduodenal, orpercutaneous endoscopic gastrostomy tube or catheter. In someembodiments, compositions disclosed herein are delivered orally or bydirect injection. In some embodiments of the methods disclosed herein,compositions are administered by a single route of administration. Insome embodiments of the methods disclosed herein, compositions areadministered by multiple routes of administration.

Kits

In some embodiments, the components of the compositions disclosed hereinare provided in kits wherein one or more of the components are containedin separate packages or containers along with instructions to combinethe components in a single composition. In some embodiments, a kitcomprises instructions to reconstitute the components in a liquidcarrier, such as water, to produce a liquid, e.g., aqueous, formulationcomprising the components. In some instances, the components of thecompositions disclosed herein are provided in a single package orcontainer with instructions to reconstitute them in a liquid carrier,such as water, to produce a liquid, e.g., aqueous, formulation. In someembodiments, the components of the compositions disclosed herein areprovided in kits wherein one or more of the components are contained inseparate packages or containers, and wherein a liquid carrier, such aswater, is also provided in a separate package or container in the kit,along with instructions to combine the components and liquid carrier ina single composition to produce a liquid, e.g., aqueous, formulation. Insome embodiments, a kit comprises instructions to administer acomposition or formulation disclosed herein orally or via a nasogastic,orogastic, nasojejunal, orojejunal, nasoduodenal, or percutaneousendoscopic gastrostomy tube or catheter to a subject, e.g., a human, totreat shock, autodigestion, multi-organ failure, ischemia, orhypoperfusion.

In certain specific embodiments, a kit comprises tranexamic acid andglucose packaged in separate containers. In some embodiments, a kitcomprises tranexamic acid, polyethylene glycol, and one or moreelectrolytes in a first container and glucose in a second container. Insome embodiments, a kit comprises tranexamic acid and polyethyleneglycol in a first container and glucose and one or more electrolytes ina second container. In some embodiments, a kit comprises tranexamic acidand electrolytes in a first container and glucose and polyethyleneglycol in a second container. In some embodiments, a kit comprisestranexamic acid in a first container and glucose, polyethylene glycol,and electrolytes in a second container. In some instances, thecontainers are made of any suitable packaging material and in any formsuitable for the distribution of pharmaceutical products.

In some embodiments, disclosed herein is a kit comprising: thecomponents tranexamic acid, PEG, glucose, and one or more electrolytes,wherein at least one of the components tranexamic acid, PEG, glucose,and one or more electrolytes is in a separate container from at leastone of the other components tranexamic acid, PEG, glucose, and one ormore electrolytes; and instructions to combine the components tranexamicacid, PEG, glucose, and one or more electrolytes in a singlecomposition. In some embodiments, a kit comprises tranexamic acid, PEG,and one or more electrolytes are in a first container, and glucose in asecond container. In some embodiments, a kit comprises instructions tocombine the tranexamic acid, PEG, one or more electrolytes, and glucose,and reconstitute them in water. In some embodiments, a kit comprises afirst container comprising about 7.8 g of tranexamic acid, about 50.3 gof PEG 3350, about 5.7 g of sodium sulfate, about 1.7 g of sodiumbicarbonate, about 1.5 g of sodium chloride, and about 0.7 g ofpotassium chloride, and a second container comprising about 40 g ofglucose. In some embodiments, a kit comprises a first containercomprising about 7.8 g of tranexamic acid, about 50.3 g of PEG 3350,about 5.7 g of sodium sulfate, about 1.7 g of sodium bicarbonate, about1.5 g of sodium chloride, and about 0.7 g of potassium chloride, asecond container comprising about 40 g of glucose, and instructions toreconstitute the tranexamic acid, PEG, glucose, and one or moreelectrolytes with water to 1000 mL. In some embodiments, a kit comprisesa first container comprising about 7.5 g of tranexamic acid, about 32.5g of PEG 3350, about 4.0 g of sodium sulfate, about 1.2 g of sodiumbicarbonate, about 1.0 g of sodium chloride, and about 0.5 g ofpotassium chloride, and a second container comprising about 28 g ofglucose. In some embodiments, a kit comprises a first containercomprising about 7.5 g of tranexamic acid, about 32.5 g of PEG 3350,about 4.0 g of sodium sulfate, about 1.2 g of sodium bicarbonate, about1.0 g of sodium chloride, and about 0.5 g of potassium chloride, asecond container comprising about 28 g of glucose, and instructions toreconstitute the tranexamic acid, PEG, glucose, and one or moreelectrolytes with water to 700 mL. In some embodiments, a kit comprisesinstructions to administer the combined components orally or via anasogastric, orogastric, nasojejunal, orojejunal, nasoduodenal, orpercutaneous endoscopic gastrostomy tube or catheter.

Testing

In some embodiments, the compositions disclosed herein are tested inanimal models that are indicative of efficacy in the treatment of shock,autodigestion, multi-organ failure, trauma, sepsis, and ischemia. Suchanimal models include but are not limited to the minipig hemorrhagicshock model, rat hemorrhagic shock, rat superior mesentery arteryocclusion shock, rodent peritonitis shock by placement of cecal materialinto the peritoneum, rodent endotoxin shock models, and rodent models ofbacterial sepsis established through a Pseudomonas infection.

EXAMPLES Example 1 Exemplary Compositions

Exemplary compositions are described in Tables 1 and 2. In someembodiments, the compositions according to the instant disclosure areprepared as a dry powder formulation and reconstituted as shown. Table 1shows a composition for reconstitution in water to 1000 mL. Table 2shows a composition for reconstitution in water to 700 mL. In someinstances, upon reconstitution, compositions are administered to apatient in need thereof, e.g., orally or directly to thegastrointestinal tract via a nasogastric, orogastric, nasojejunal,orojejunal, nasoduodenal, or percutaneous endoscopic gastrostomy tube orcatheter.

TABLE 1 Amount (g) for Concentration (wt %) in Component 1000 mLsolution 1000 mL aqueous solution Tranexamic acid 7.8 ± 10% 0.78 ± 10%PEG 3350 50.3 ± 10%  5.03 ± 10% Sodium Sulfate 5.7 ± 10% 0.57 ± 10%Sodium Bicarbonate 1.7 ± 10% 0.17 ± 10% Sodium Chloride 1.5 ± 10% 0.15 ±10% Potassium Chloride 0.7 ± 10% 0.07 ± 10% Glucose  40 ± 10%  4.0 ± 10%

TABLE 2 Amount (g) for Concentration (wt %) in Component 700 mL solution700 mL aqueous solution Tranexamic acid 7.5 ± 10%  1.1 ± 10% PEG 335032.5 ± 10%   4.6 ± 10% Sodium Sulfate 4.0 ± 10% 0.57 ± 10% SodiumBicarbonate 1.2 ± 10% 0.17 ± 10% Sodium Chloride 1.0 ± 10% 0.15 ± 10%Potassium Chloride 0.5 ± 10% 0.07 ± 10% Glucose  28 ± 10%  4.0 ± 10%

Example 2 Superior Mesentery Artery Occlusion (SMAO) Shock Studies withFormulations Administered via Oral Gavage

The SMAO model was used to assess the ability of a representativecomposition comprising PEG 3350 (Representative Formulation 1) and acomparative composition without PEG 3350 (Comparative Formulation 1) topreserve the structural integrity of the gastrointestinal tract underischemic conditions when administered by oral gavage.

Formulation Preparation

The materials used to prepare the formulations and their sources areshown in Table 3. All materials used were USP grade. As shown in Table3, Representative Formulation 1 comprises tranexamic acid, electrolytes,PEG 3350, and glucose, and Comparative Formulation 1 comprisestranexamic acid, electrolytes, and glucose.

TABLE 3 Representative Comparative Component Formulation 1 Formulation 1Source Tranexamic acid 0.043 g 0.043 g Daiichi Sankyo PEG 3350 0.287 g 0.0 g OTC clinical grade Miralax Sodium Sulfate 0.033 g 0.033 gSigma-Aldrich (Anhydrous) Sodium 0.010 g 0.010 g Sigma-AldrichBicarbonate Sodium Chloride 0.009 g 0.009 g Sigma-Aldrich Potassium0.004 g 0.004 g Sigma-Aldrich Chloride Glucose 0.229 g 0.229 gSigma-Aldrich Water 3.629 g 3.629 g Sterile water for injection TotalSolution  4.000 mL  4.000 mL

Rats and Diet

Male WISTAR rats with a weight of 360-400 grams were purchased fromCharles River Laboratories, located in Wilmington, Mass. All rats weremaintained on a 2018 Teklad Global 18% Protein Rodent Diet (Harlan, SanDiego, Calif., USA) and water throughout the study period.

Formulation Administration

Food was removed from the cage the evening prior to surgery. Rats had adlib access to drinking water while in the home cage the evening prior tosurgery. During administration of the formulations, rats were restrainedand given 4 mL of Representative Formulation 1 or ComparativeFormulation 1 by oral gavage. After administration of the testformulations, rats were returned to their home cage and given ad libaccess to water. After a 3 hour period, the rats were prepared toundergo experimentally induced shock.

Anesthesia and Preoperative Preparation

Animals were anesthetized with ketamine/xylazine (75/4 mg/kg, I.M.).Supplemental anesthesia (ketamine/xylazine 10% initial dose, I.M.) wasadministered as indicated following response to tail/toe pinch.Anesthesia was maintained throughout the experimental shock period.

Rats were secured in a supine position to a temperature controlled(water circulating heat pump) operating table. The animals weremaintained at 37° C. throughout the procedures.

All surgical procedures were performed using aseptic techniques. Steriledrapes, heat sterilized instruments, and surgical apparel (gown, facemask, and gloves) were used. The surgical sites on the abdomen and leftgroin were shaved and cleaned with betadine followed by 70% alcohol.

SMAO Procedures

Following anesthetization, the superior mesentery artery was located andtied off (occluded) to prevent blood flow to the intestine and initiatea 30 minute shock/hypoperfusion period. The surgical site was coveredwith moistened sterile gauze during the entire SMAO shock period. Afterthe 30 minute period, the SMAO was untied (occlusion removed). Perfusionwas resumed for a period of 2 hours, followed by sacrifice of theanimals.

Necropsy and Histological Processing

The intestines were then harvested by tying off both ends, injecting a10% neutral buffered formalin solution with a 30 gauge needle, andstoring the intestine in a jar filled with 10% neutral bufferedformalin.

Following at least 24 hours of incubation in formalin, an approximate 5cm by 5 cm section of the ileum (at approximately ⅚ the length of thesmall intestine) was excised for structural analysis. The tissue samplewas adhered to a cardboard backing and mounted for sectioning.Intestinal cross sections of 15-20 microns thickness were created on aVibratome Series 3000 sectioning system. Free floating sections werewashed overnight in water to remove formalin. Sections were then freefloating stained with Alcian blue (pH 2.5) (Diagnostic BioSystems,Catalog No. KT 003) and mounted on slides for analysis.

Tissue Analysis

A Leitz Wetzlar Dialux 20 microscope (Wetzlar, West Germany) and20×objective was used to image tissue sections. Still images of thetissue were captured with a Spot Insight Gigabit Camera, Model No. 35.2,Diagnostic Instruments, Inc. (Sterling Heights, Mich.) and includedsoftware. Images were stored as TIFF files with no compression used.Images were loaded into Photoshop Elements 13 and enhanced to sharpenthe contours of the villi. To quantify the extent of damage to thevilli, villi were classified as damaged when either of the followingcriteria was met: 1) Villi tips were broken away or structural damage toany portion of the villi; or 2) Goblet cells (normally stained blue)were practically non-existent (≦3 goblet cells with no stain) from thebase to the villi tip

The Photoshop Text tool was used to place an n (for no damage) or a d(for damage) in proximity to each individual villi for each tissue crosssection. Where a determination of damage was inconclusive, the villiwere excluded from the analysis. These inconclusive villi were less than5% of the total villi analyzed. An image demonstrating theidentification methodology is in FIG. 1, which shows a cross section ofthe small intestine from a rat treated with an enteral formulation.Healthy villi are marked with n and damaged villi are marked with d.

Results

A total of eight rats were tested. Four received RepresentativeFormulation 1 by oral gavage, and four rats received ComparativeFormulation 1 by oral gavage. Representative micrographs of the villiafter administration of the formulations and shock induction are shownin FIGS. 2A and 2B. FIG. 2A shows a cross section of the small intestineof a rat treated with Representative Formulation 1. The villi in FIG. 2Aappear healthy and structurally intact as the entire length of the villiare visible and completely covered in goblet cells. FIG. 2B shows across section of the small intestine of a rat treated with ComparativeFormulation 1. The villi in FIG. 2B appear to be structurally damagedwith missing villi tips and atypical goblet cell staining.

Quantification of villi that were structurally intact afteradministration of the formulations and shock induction are shown inTables 4 and 5 and FIG. 3. Table 4 shows the individual rat data for thequantification of the structurally intact villi. Table 5 summarizes thetotal intact villi and damaged villi observed after administration ofthe formulations and shock induction. FIG. 3 shows the mean percentageof villi intact per rat after administration of the formulations andshock induction. 92.6% of villi were intact across all rats thatreceived Representative Formulation 1, whereas only 52.8% of the villiwere intact across all rats that received Comparative Formulation 1.These results are consistent with the mean values calculated from thetotal villi observed in Table 5.

TABLE 4 Rats Treated with Rats Treated with Representative ComparativeFormulation 1 % Intact Villi Formulation 1 % Intact Villi Rat #11 90.9%Rat #12 50.9% Rat #13 90.2% Rat #15 48.9% Rat #14 91.3% Rat #16 48.8%Rat #18 97.9% Rat #17 62.5% Mean 92.6% Mean 52.8% SEM (+/−) 1.8% SEM(+/−) 3.3%

TABLE 5 Rats Treated with Rats Treated with Representative ComparativeFormulation 1 Formulation 1 Number of Intact Villi 176 94 Number ofDamaged Villi 14 85 Total Villi 190 179 % Intact 92.6% 52.5%

Example 3 SMAO Shock Studies with Formulations Administered via DirectEnteral Injection

The SMAO model was used to assess the ability of a representativecomposition comprising glucose (Representative Formulation 2) and acomparative composition without glucose (Comparative Formulation 2) topreserve the structural integrity of the gastrointestinal tract underischemic conditions when administered by direct enteral injection.

Formulation Preparation

The materials used to prepare the formulations and their sources areshown in Table 6. All materials used were USP grade. As shown in Table6, the Representative Formulation 2 comprises tranexamic acid,electrolytes, PEG 3350, and glucose, and Comparative Formulation 2comprises tranexamic acid, electrolytes, and PEG 3350.

TABLE 6 Representative Comparative Component Formulation 2 Formulation 2Source Tranexamic acid 0.182 g 0.182 g Daiichi Sankyo PEG 3350 1.222 g1.222 g OTC clinical grade Miralax Sodium Sulfate 0.138 g 0.138 gSigma-Aldrich (Anhydrous) Sodium 0.041 g 0.041 g Sigma-AldrichBicarbonate Sodium Chloride 0.036 g 0.036 g Sigma-Aldrich Potassium0.017 g 0.017 g Sigma-Aldrich Chloride Glucose 0.971 g  0.0 gSigma-Aldrich Water 15.421 g  15.421 g  Sterile water for injectionTotal Solution  17.000 mL  17.000 mL

Rats and Diet

Male WISTAR rats with a weight of 360-400 grams were purchased fromCharles River Laboratories, located in Wilmington, Mass. All rats weremaintained on a 2018 Teklad Global 18% Protein Rodent Diet (Harlan, SanDiego, Calif., USA) and water throughout the study period.

Formulation Administration

Food was removed from the cage the evening prior to surgery. Rats had adlib access to drinking water while in the home cage the evening prior tosurgery. Following anesthesia, an incision was made in the midline ofthe abdomen for isolation of the small intestine. Rats were administered17 mL of either Representative Formulation 2 or Comparative Formulation2 via direct injection into the intestine using a 30 gauge needle.Following formulation administration, the rats were subjected toexperimentally induced shock via the SMAO procedure.

Anesthesia and Preoperative Preparation

Animals were anesthetized with ketamine/xylazine (75/4 mg/kg, I.M.).Supplemental anesthesia (ketamine/xylazine 10% initial dose, I.M.) wasadministered as indicated following response to tail/toe pinch.Anesthesia was maintained throughout the experimental shock period.

Rats were secured in a supine position to a temperature controlled(water circulating heat pump) operating table. The animals weremaintained at 37° C. throughout the procedures.

All surgical procedures were performed using aseptic techniques. Steriledrapes, heat sterilized instruments, and surgical apparel (gown, facemask, and gloves) were used. The surgical sites on the abdomen and leftgroin were shaved and cleaned with betadine followed by 70% alcohol.

SMAO Procedures

To initiate the model, following anesthesia the superior mesenteryartery was located and tied off (occluded) to prevent blood flow to theintestine and initiate a 30 minute shock/hypoperfusion period. Thesurgical site was covered with moistened sterile gauze during the entireSMAO shock period. After the 30 minute period, the SMAO was untied(occlusion removed). Perfusion was resumed for a period of 2 hours,followed by sacrifice of the animals.

Necropsy and Histological Processing

The intestines were then harvested by tying off both ends, injecting a10% neutral buffered formalin solution with a 30 gauge needle, andstoring the intestines in a jar filled with 10% neutral bufferedformalin.

Following at least 24 hours of incubation in formalin, an approximate 5cm by 5 cm section of the ileum (at approximately ⅚ the length of thesmall intestine) was excised for structural analysis. The tissue samplewas adhered to a cardboard backing and mounted for sectioning.Intestinal cross sections of 15-20 microns thickness were created on aVibratome Series 3000 sectioning system. Free floating sections werewashed overnight in water to remove formalin. Sections were then freefloating stained with Alcian blue (pH 2.5) (DiagnosticBioSystems,Catalog No. KT 003) and mounted on slides for analysis.

Tissue Analysis

A Leitz Wetzlar Dialux 20 microscope (Wetzlar, West Germany) and20×objective was used to image tissue sections. Still images of thetissue were captured with a Spot Insight Gigabit Camera, Model No. 35.2,Diagnostic Instruments, Inc. (Sterling Heights, Mich.) and includedsoftware. Images were stored as TIFF files with no compression used.Images were loaded into Photoshop Elements 13 and enhanced to sharpenthe contours of the villi. To quantify the extent of damage to thevilli, villi were classified as damaged when either of the followingcriteria were met: 1) Villi tips were broken away or structural damageto any portion of the villi; or 2) Goblet cells (normally stained blue)were practically non-existent (≦3 goblet cells with no stain) from thebase to the villi tip

The Photoshop Text tool was used to place an n (for no damage) or a d(for damage) in proximity to each individual villi for each tissue crosssection. Where a determination of damage was inconclusive, the villiwere excluded from the analysis. These inconclusive villi were less than5% of the total villi analyzed. An image demonstrating theidentification methodology is in FIG. 1, which shows a cross section ofthe small intestine from a rat treated with an enteral formulation.Healthy villi are marked with n and damaged villi are marked with d.

Results

A total of eight rats were tested. Four rats received RepresentativeFormulation 2 by direct enteral injection, and four rats receivedComparative Formulation 2 by direct enteral injection. Representativemicrographs of the villi after administration of the formulations andshock induction are shown in FIGS. 4A and 4B. FIG. 4A shows a crosssection of the small intestine of a rat treated with RepresentativeFormulation 2. The villi in FIG. 4A appear healthy and structurallyintact as the entire length of the villi are visible and completelycovered in goblet cells. FIG. 4B shows a cross section of the smallintestine of a rat treated with Comparative Formulation 2. The villi inFIG. 4B appear to be structurally damaged with missing villi tips andatypical goblet cell staining.

Quantification of villi that are structurally intact afteradministration of the formulations and shock induction are shown inTables 7 and 8 and FIG. 5. Table 7 shows the individual rat data for thequantification of the structurally intact villi. Table 8 summarizes thetotal intact villi and damaged villi observed after administration ofthe formulations and shock induction. FIG. 5 shows the mean percentageof villi intact per rat after administration of the formulations andshock induction. 83.4% of villi were intact across all rats thatreceived Representative Formulation 2, whereas only 51.3% of the villiwere intact across all rats that received Comparative Formulation 2.These results are consistent with the mean values calculated from thetotal villi observed in Table 8.

TABLE 7 Rats Treated with Rats Treated with Representative ComparativeFormulation 2 % Intact Villi Formulation 2 % Intact Villi Rat #1 85.3%Rat #2 46.3% Rat #4 88.2% Rat #3 54.1% Rat #6 76.0% Rat #5 51.3% Rat #884.2% Rat #1 53.7% Mean 83.4% Mean 51.3% SEM (+/−) 2.6% SEM (+/−) 1.8%

TABLE 8 Rats Treated with Rats Treated with Representative ComparativeFormulation 2 Formulation 2 Number of Intact Villi 110 106 Number ofDamaged Villi 21 102 Total Villi 131 208 % Intact 84.0% 51.0%

Example 4 Hemorrhagic Shock Studies with Formulations Administered viaDirect Stomach Injection

The hemorrhagic shock model was used to assess the ability of arepresentative composition comprising PEG 3350 (RepresentativeFormulation 3) and a comparative composition without PEG 3350(Comparative Formulation 3) to preserve the structural integrity of thegastrointestinal tract under hemorrhagic conditions when administered bydirect stomach injection.

Formulation Preparation

The materials used to prepare the formulations and their sources areshown in Table 9. All materials used were USP grade. As shown in Table9, the Representative Formulation 3 comprises tranexamic acid,electrolytes, PEG 3350, and glucose, and Comparative Formulation 3comprises tranexamic acid, electrolytes, and glucose.

TABLE 9 Representative Comparative Component Formulation 3 Formulation 3Source Tranexamic acid 0.043 g 0.043 g Daiichi Sankyo PEG 3350 0.287 g 0.0 g OTC clinical grade Miralax Sodium Sulfate 0.033 g 0.033 gSigma-Aldrich (Anhydrous) Sodium 0.010 g 0.010 g Sigma-AldrichBicarbonate Sodium Chloride 0.009 g 0.009 g Sigma-Aldrich Potassium0.004 g 0.004 g Sigma-Aldrich Chloride Glucose 0.229 g 0.229 gSigma-Aldrich Water 3.629 g 3.629 g Sterile water for injection TotalSolution  4.000 mL  4.000 mL

Rats and Diet

Male WISTAR rats with a weight of 320-400 grams were purchased fromCharles River Laboratories, located in Wilmington, Mass. All rats weremaintained on Charles River Laboratories feed and provided water adlibitum throughout the study period.

Formulation Administration

Food was removed from the cage the evening prior to surgery. Afterplacement of catheters, a small skin incision in the abdomen was madefor isolation of the stomach. Following stabilization afterexperimentally induced shock via the hemorrhagic shock procedure, ratswere administered 4 mL of either Representative Formulation 3 orComparative Formulation 3 via a direct injection into the middle of thestomach.

Anesthesia and Preoperative Preparation

Animals were anesthetized with ketamine (75 mg/kg, I.M.). Anesthesia wasmaintained throughout the experimental shock period.

Rats were secured in a supine position to a temperature controlled(water circulating heat pump) operating table. The animals weremaintained at 37° C. throughout the procedures. Vital signs (systemicblood pressure or respiratory rate, body temperature) were monitoredthroughout the procedures.

All surgical procedures were performed using aseptic techniques. Steriledrapes, heat sterilized instruments, and surgical apparel (gown, facemask, and gloves) were used. The surgical sites on the abdomen and leftgroin were shaved and cleaned with betadine followed by 70% alcohol.

Hemorrhagic Shock Procedures

To initiate the model, rats were anesthetized with ketamine (75 mg/kg,I.M.). Abdominal and inguinal regions were shaved and disinfected withalcohol. The right femoral artery was cannulated. The surgical site wascovered with moistened sterile gauze during entire hemorrhagic shockperiod. Hemorrhagic shock was initiated by reduction of blood volume(about 40% of whole blood volume based on 6% body weight) to achieve ablood pressure of 35 mmHg (47.58 cm H₂O) for a period of 2 hours.Briefly, each rat was heparinized with minimal concentrations of sodiumheparin (0.5 USP units/ml of blood volume estimated as 6% body weight)to prevent blood coagulation during the procedure. The right femoralartery was connected with a 10 cc syringe. About 6 ml of blood waswithdrawn from the femoral artery over a period of about 5-10 minutes.The syringe was then placed at 47.58 cm high above the rat body level.The syringe served as a blood reservoir that regulated blood pressure at47.58 cm H₂O (35 mm Hg) automatically. If the blood pressure was above47.58 cm H₂O, blood flowed into the blood reservoir. If the bloodpressure was under 47.58 cm H₂O, the blood from the blood reservoir wasinfused into blood stream circulation. Once mean arterial pressure (MAP)was stabilized, either Representative Formulation 3 or ComparativeFormulation 3 was injected into the middle of the stomach.

Necropsy and Histological Processing

The intestines were then harvested by tying off both ends, injecting a10% neutral buffered formalin solution with a 30 gauge needle, andstoring the intestines in a jar filled with 10% neutral bufferedformalin.

Following at least 24 hours of incubation in formalin, an approximate 5cm by 5 cm section of the ileum (at approximately ⅚ the length of thesmall intestine) was excised for structural analysis. The tissue samplewas adhered to a cardboard backing and mounted for sectioning.Intestinal cross sections of 15-20 microns thickness were created on aVibratome Series 3000 sectioning system. Free floating sections werewashed overnight in water to remove formalin. Sections were then freefloating stained with Alcian blue (pH 2.5) (DiagnosticBioSystems,Catalog No. KT 003) and mounted on slides for analysis.

Tissue Analysis

A Leitz Wetzlar Dialux 20 microscope (Wetzlar, West Germany) and20×objective was used to image tissue sections. Still images of thetissue were captured with a Spot Insight Gigabit Camera, Model No. 35.2,Diagnostic Instruments, Inc. (Sterling Heights, Mich.) and includedsoftware. Images were stored as TIFF files with no compression used.Images were loaded into Photoshop Elements 13 and enhanced to sharpenthe contours of the villi. To quantify the extent of damage to thevilli, villi were classified as damaged when either of the followingcriteria were met: 1) Villi tips were broken away or structural damageto any portion of the villi; or 2) Goblet cells (normally stained blue)were practically non-existent (≦3 goblet cells with no stain) from thebase to the villi tip

The Photoshop Text tool was used to place an n (for no damage) or a d(for damage) in proximity to each individual villi for each tissue crosssection. Where a determination of damage was inconclusive, the villiwere excluded from the analysis. These inconclusive villi were less than5% of the total villi analyzed. An image demonstrating theidentification methodology is in FIG. 1, which shows a cross section ofthe small intestine from a rat treated with an enteral formulation.Healthy villi are marked with n and damaged villi are marked with d.

Results

A total of eight rats were tested. Four rats received RepresentativeFormulation 3 by direct stomach injection, and four rats receivedComparative Formulation 3 by direct stomach injection. Representativemicrographs of the villi after administration of the formulations andshock induction are shown in FIGS. 6A and 6B. FIG. 6A shows a crosssection of the small intestine of a rat treated with RepresentativeFormulation 3. The villi in FIG. 6A appear healthy and structurallyintact as the entire length of the villi are visible and completelycovered in goblet cells. FIG. 6B shows a cross section of the smallintestine of a rat treated with Comparative Formulation 3. The villi inFIG. 6B appear to be structurally damaged.

Quantification of villi that are structurally intact afteradministration of the formulations and shock induction are shown inTables 10 and 11 and FIG. 7. Table 10 shows the individual rat data forthe quantification of the structurally intact villi. Table 11 summarizesthe total intact villi and damaged villi observed after administrationof the formulations and shock induction. FIG. 7 shows the meanpercentage of villi intact per rat after administration of theformulations and shock induction. 88.8% of villi were intact across allrats that received Representative Formulation 3, whereas only 64.1% ofthe villi were intact across all rats that received ComparativeFormulation 3. These results are consistent with the mean valuescalculated from the total villi observed in Table 11.

TABLE 10 Rats Treated with Rats Treated with Representative ComparativeFormulation 3 % Intact Villi Formulation 3 % Intact Villi Rat #701 90.7%Rat #802 65.6% Rat #704 83.3% Rat #805 66.7% Rat #705 91.1% Rat #80662.7% Rat #706 90.0% Rat #807 61.5% Mean 88.8% Mean 64.1% SEM (+/−) 1.8%SEM (+/−) 1.2%

TABLE 11 Rats Treated with Rats Treated with Representative ComparativeFormulation 3 Formulation 3 Number of Intact Villi 171 105 Number ofDamaged Villi 23 59 Total Villi 194 164 % Intact 88.1% 64.0%

Example 5 Clinical Study for the Treatment of Septic Shock PrimaryObjective

This is a multicenter, randomized, double-blind, parallel,placebo-controlled Phase 2 clinical study of septic shock patients todetermine whether enteral administration of a formulation comprisingtranexamic acid, PEG, glucose, and one or more electrolytes increasesthe number of days alive without cardiovascular, pulmonary, or renalreplacement therapy through Day 28 compared to Placebo.

Secondary Objectives

The secondary safety objective of this study is to assess safety andtolerability of experimental composition in patients with septic shock.

Eligibility (1) First episode of documented or suspected sepsis ofperitoneal/abdominal, soft tissue, blood, or community acquired lungorigin. (2) Must have septic shock requiring vasopressors despiteadequate fluid resuscitation of 30 mL/kg crystalloid or colloidequivalent, for either an SBP≦90 mmHg or a MAP≦65 mmHg (i.e. must havebeen unable to maintain adequate blood pressure despite adequate fluidresuscitation). (3) Age 18 to 75 years

Study Design

The study is composed of four periods: (1) Screening: This period beginswhen the patient has documented or suspected sepsis ofperitoneal/abdominal, soft tissue, blood, or community acquired lungorigin and is unable to maintain adequate blood pressure (BP, systolicBP [SBP]>90 mmHg or a mean arterial pressure [MAP]>65 withoutvasopressor support) despite intravenous fluid resuscitation. Enteralstudy drug administration must start within 4 hours of randomization andno later than 24 hours after the onset of shock. (2) Intervention: Thisperiod begins with the first administration of the test formulation orplacebo and continues throughout treatment duration, up to 8 dayspending patient refusal to take study drug, exit from hospital or death.There are no food or fluid restrictions. However, during the first 48hours following enrollment, physicians are encouraged to delay enteralnutrition. If a patient is moved from ICU and still in the hospital,study drug administration should continue until 8 doses have beenadministered. (3) Post-intervention: This period begins after study drugadministration is complete and continues through Study Day 28 or untilthe patient is discharged from the hospital (if before Day 28). If apatient has been discharged from the study hospital before Study Day 28,site personnel will contact the patient or surrogate, caregiver, familymember, physician, or healthcare facility to obtain the patient'ssurvival status, organ support and functional outcome assessment. (4)Follow-up: Site personnel will contact the patient, surrogate,caregiver, family member, or patient's other healthcare providers todetermine survival status on Day 90.

All randomized patients will be divided between the two treatment armsin a 1:1 ratio stratified by highest total SOFA score during thescreening period (known at the time of randomization); and then bypercent change in serum lactate between the first and subsequent lactatemeasurements (separated by at least 4 hours to be used to qualify forrandomization).

A total of 250 patients are enrolled. The 700 mL aqueous solutionformulation shown in Table 2 is administered orally or via anasogastric, orogastric, nasojejunal, orojejunal, nasoduodenal, orpercutaneous endoscopic gastrostomy tube or catheter to patients in theexperimental arm. Patients in the placebo arm of the study receive 700mL of a placebo solution that does not comprise tranexamic acid orallyor via a nasogastric, orogastric, nasojejunal, orojejunal, nasoduodenal,or percutaneous endoscopic gastrostomy tube or catheter. Daily treatmentis administered continuously or intermittently spread over an 8 to 24hour period. 700 mL of experimental product or placebo is administeredevery 24 hours. Treatment is administered daily on Study Days 1-8,barring death or hospital discharge. Depending on the start time of theinitial administration (infusion) on Study Day 1, the finaladministration extends into Study Day 9.

Efficacy Endpoints

The primary efficacy endpoint is the number of days alive withoutcardiovascular, renal, or pulmonary organ support through Day 28.Patients are classified as having organ support if organ support isrequired through the use of: Mechanical ventilation; Vasopressors tomaintain adequate BP, or Renal replacement therapy.

The secondary efficacy endpoint is mortality rate: Date of death will berecorded for all patients who have died on or before Study Day 90. The7-day, 28-day, and 90-day mortality and survival rates will beevaluated.

Results

The aqueous solution formulation shown in Table 2 is safe andwell-tolerated by patients in the experimental arm. Patients in theexperimental arm exhibit an increase in the number of days withoutcardiovascular, renal, or pulmonary support through Day 28 of the studyas compared to patients in the placebo arm. Patients in the experimentalarm exhibit a decrease in the rates of mortality on day 90 of the studyas compared to mortality rates of patients in the placebo arm.

Example 6 Clinical Study for the Treatment of Shock and MultiorganDysfunction after Cardiovascular Surgery Primary Objective

This is a multicenter, randomized, double-blind, parallel,placebo-controlled, Phase 2 clinical study to determine whether enteraladministration of a formulation comprising tranexamic acid, PEG,glucose, and one or more electrolytes prior to high risk cardiovascularsurgery increases the number of days alive without cardiovascular,renal, or pulmonary dysfunction through Day 14 compared to Placebo.

Study Design

All high risk cardiovascular surgery randomized patients will be dividedbetween the 2 treatment groups in a 1:1 ratio stratified by: Age (≦64 or≧65 years of age); STS Cardiac Score, and Procedure.

The study is composed of four periods: (1) Screening and randomization(not to exceed 4 weeks): prior to cardiovascular surgery. (2)Intervention: will begin with the first enteral administration of studydrug 6-12 hours prior to surgery (Day 0). Treatment should continue fora minimum of 7 days (pending patient refusal to take study drug, exitfrom hospital, or mortality). In some cases, patients with continuedorgan dysfunction remain on study drug for up to 10 days as long asorgan dysfunction persists. (3) Post-intervention in-hospital: willstart after study drug administration is stopped (Day 8) and willcontinue through Day 14 or until the patient is discharged from thehospital. (4) Follow-up: the patient will be contacted by phone toassess functional outcomes at Day 28.

A total of 100 patients are enrolled. The 700 mL aqueous solutionformulation shown in Table 2 or a Placebo that does not comprisetranexamic acid is administered orally or via a nasogastric, orogastric,nasojejunal, orojejunal, nasoduodenal, or percutaneous endoscopicgastrostomy tube or catheter to patients on Days 0-7. If a patientcontinues to demonstrate organ dysfunction, the physician will continuetreatment for a maximum of 10 days for some cases. Patients,investigators, persons performing the assessments, and data analystsremain blinded to the identity of the treatment from time ofrandomization until database lock.

Efficacy Endpoints

The primary efficacy endpoint is the number of days alive withoutcardiovascular, renal or pulmonary organ support through Day 14.Patients are classified as requiring organ support if organ support isprovided through the use of: Mechanical ventilation; Vasopressors tomaintain adequate blood pressure (BP); or Renal replacement therapy(hemodialysis, peritoneal dialysis or continuous venous hemofiltration).

The secondary efficacy endpoint is mortality rate: date of death will berecorded for all patients who have died on or before Study Day 28 andDay 90. The 28-day and 90-day mortality and survival rates will beevaluated.

Results

The aqueous solution formulation shown in Table 2 is safe andwell-tolerated by patients in the experimental arm. Patients in theexperimental arm exhibit an increase in the number of days alive withoutcardiovascular, renal, or pulmonary dysfunction through Day 14 comparedto Placebo. Patients in the experimental arm exhibit a decrease in therates of mortality on day 90 of the study as compared to mortality ratesof patients in the placebo arm.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein are employed in practicing the invention. It is intended that thefollowing claims define the scope of the invention and that methods andstructures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A composition comprising about 1.0 wt % to about1.2 wt % of tranexamic acid, about 4.2 wt % to about 5.1 wt % ofpolyethylene glycol, about 3.6 wt % to about 4.4 wt % of glucose, andone or more electrolytes.
 2. The composition of claim 1, comprisingabout 4.4 wt % to about 4.8 wt % of polyethylene glycol and about 3.8 wt% to about 4.2 wt % of glucose.
 3. The composition of claim 1, whereinthe one or more electrolytes comprise sodium sulfate, sodiumbicarbonate, sodium chloride, and potassium chloride.
 4. The compositionof claim 1, wherein the one or more electrolytes comprise about 0.51 wt% to about 0.63 wt % of sodium sulfate, about 0.16 wt % to about 0.19 wt% of sodium bicarbonate, about 0.13 wt % to about 0.17 wt % of sodiumchloride, and about 0.06 wt % to about 0.09 wt % of potassium chloride.5. The composition of claim 1, wherein the one or more electrolytescomprise about 0.57 wt % of sodium sulfate, about 0.17 wt % of sodiumbicarbonate, about 0.15 wt % of sodium chloride, and about 0.07 wt % ofpotassium chloride.
 6. The composition of claim 1, wherein thepolyethylene glycol has an average molecular weight of about 2000, about3000, about 3350, or about
 4000. 7. The composition of claim 1, whereinthe composition is an aqueous solution.
 8. The composition of claim 7,comprising about 630 mL to about 770 mL of the aqueous solution.
 9. Akit to form the composition of claim 1, wherein the kit comprises: (i) afirst container which comprises tranexamic acid, polyethylene glycol,and one or more electrolytes; (ii) a second container which comprisesglucose; and (iii) instructions to combine the components of the firstcontainer and the components of the second container to form thecomposition.
 10. A kit to form the composition of claim 1, wherein thekit comprises: (i) a first container which comprises tranexamic acid andpolyethylene glycol; (ii) a second container which comprises glucose andone or more electrolytes; and (iii) instructions to combine thecomponents of the first container and the components of the secondcontainer to form the composition.
 11. A kit to form the composition ofclaim 1, wherein the kit comprises: (i) a first container whichcomprises tranexamic acid; (ii) a second container which comprisespolyethylene glycol, glucose, and one or more electrolytes; and (iii)instructions to combine the components of the first container and thecomponents of the second container to form the composition.
 12. A kit toform the composition of claim 1, wherein the kit comprises: (i) a firstcontainer which comprises tranexamic acid and one or more electrolytes;(ii) a second container which comprises polyethylene glycol and glucose;and (iii) instructions to combine the components of the first containerand the components of the second container to form the composition. 13.A composition comprising about 1.0 wt % to about 1.2 wt % of tranexamicacid, about 4.2 wt % to about 5.1 wt % of polyethylene glycol, about 2.5wt % to about 6.0 wt % of glucose, and one or more electrolytes.
 14. Thecomposition of claim 13, comprising about 3.5 wt % to about 5.5 wt % ofglucose.
 15. The composition of claim 13, comprising about 1.1 wt % oftranexamic acid, about 4.2 wt % of polyethylene glycol, about 5.0 wt %of glucose.
 16. The composition of claim 13, wherein the one or moreelectrolytes comprise sodium sulfate, sodium bicarbonate, sodiumchloride, and potassium chloride.
 17. A composition comprising about 7.2grams to about 7.8 grams of tranexamic acid, about 29.3 grams to about35.8 grams of polyethylene glycol, about 25 grams to about 40 grams ofglucose, and one or more electrolytes.
 18. The composition of claim 17,comprising about 7.4 grams to about 7.6 grams of tranexamic acid, about29.3 grams to about 33.5 grams of polyethylene glycol, and about 27grams to about 37 grams of glucose.
 19. The composition of claim 17,comprising about 7.5 grams of tranexamic acid, about 29.5 grams ofpolyethylene glycol, and about 35 grams of glucose.
 20. The compositionof claim 17, wherein the one or more electrolytes comprise sodiumsulfate, sodium bicarbonate, sodium chloride, and potassium chloride